Interferon-induced 2'-5' adenylate synthetase in vivo and interferon production in vitro by lymphocytes from systemic lupus erythematosus patients with and without circulating interferon.

The interferon (IFN)-induced enzyme 2-5A synthetase was elevated in mononuclear cells from both serum IFN-positive and -negative systemic lupus erythematosus (SLE) patients. This suggests that a much higher percentage of patients than previously thought produce endogenous IFN. These results may partly explain findings that mononuclear cells from SLE patients are deficient in IFN production in vitro in response to certain IFN inducers. Although normal lymphocytes can produce an acid-labile alpha IFN after stimulation with C. parvum in vitro, the reason for endogenous production of this unusual alpha IFN by SLE patients remains unknown.

Present status and future prospects for HIV therapies.

Since the discovery of human immunodeficiency virus (HIV) in 1983, significant progress has been made toward the discovery, development, and licensing of anti-HIV drugs. In vitro screens against whole virus are now being complemented by screens against specific viral targets, resulting in the development of clinical candidates acting at several critical stages of the viral life cycle. Despite these advances, clinical therapy remains largely palliative. In addition, it has recently been recognized that HIV resistance to most drugs may pose even greater obstacles. Moreover, emerging data on immunopathogenesis raise the possibility that even if virus was eliminated from an infected individual, the patient's immune system might not be capable of restoration to normal function. In the face of such obstacles, deeper insights into the pathogenic mechanisms of disease, aggressive exploitation of those mechanisms for therapeutic gain, and continued commitment of both public and private sectors to support and collaborate in this research are needed.

Progress in HIV vaccine development.

Recent advances in HIV vaccine development include initiation of the first efficacy trials and substantial expansion of the preclinical pipeline. Several preclinical candidate vaccines have induced strong cellular immune responses and provided impressive protection against AIDS in non-human primate models; however, candidates that induce broadly neutralizing antibodies remain elusive.

Increasing incidence of anorexia nervosa in the female population of northeast Scotland.

OBJECTIVE: The aim of the study was to determine whether there has been an increase in the incidence of anorexia nervosa in the female population in the northeast of Scotland since the 1960s. METHOD: Standardized diagnostic criteria were applied to the case records of female subjects who had been diagnosed as suffering from anorexia nervosa and had presented for the first time to psychiatric services between 1965 and 1991 or had been admitted for the first time to a general hospital between 1970 and 1991. Age-standardized annual incidence rates were calculated from 1965 through 1991. As a broad measure of severity, the weights of patients in 3 early years of the study, 1970-1972, were compared with those of patients in the last 3 years, 1989-1991. RESULTS: Over the 27-year period studied, 287 patients received confirmed diagnoses of anorexia nervosa, and the mean annual increase in incidence was 5.3%. The rate of increase was highly statistically significant. Comparison of weights at presentation showed a trend for patients presenting in 1970-1972 to be lighter than those presenting in 1989-1991. CONCLUSIONS: Rates of referral for female subjects with anorexia nervosa have greatly increased since the 1960s. These rates likely reflect a genuine increase in incidence, but the data suggest that less severely ill patients are now being referred.

Effects of zidovudine on Friend virus complex infection in Rfv-3r/s genotype-containing mice used as a model for HIV infection.

Infection with the Friend virus complex (FV) in (B10.A x A/WySn)F1 mice containing the Rfv-3r/s genotype results in several disease manifestations analogous to those seen in patients with acquired immune deficiency syndrome, predominantly high levels of specific antibody and low levels of infectious virus with eventual retroviral disease-induced death of the host. Other immunologic manifestations of FV infection in this murine host included inhibition of percent total T, T-helper, and T-suppressor/cytotoxic cells of total splenic lymphocytes and phytohemagglutinin-induced response of spleen cells. Interleukin-1 production was not affected but the numbers of splenic B cells were increased by the infection. 3'-Azido-3'-deoxythymidine (zidovudine, AZT) administered (a) intraperitoneally three times daily for 24 days beginning 4 h after virus inoculation in doses of 60 to 480 mg/kg/day, (b) in drinking water for 22 days beginning 4 h after virus inoculation in doses of 22 to 216 mg/kg/day, or (c) in drinking water for 29 days beginning 6 days after virus inoculation in doses of 22 to 216 mg/kg/day markedly inhibited FV-induced disease. In the mice receiving early-initiated AZT therapy, FV-induced splenomegaly and hematocrit values were inhibited and infectious centers in the spleen and FV titers in the plasma were reduced to below detectable levels at the higher AZT dosage levels. The percent of total T cells in splenic lymphocytes was increased in the infected, AZT-treated mice. In the intraperitoneal experiment, FV disease-induced death was prevented by treatment with all doses of AZT. Neutralizing antibody to FV was significantly reduced in all AZT-treated groups. Toxicologic manifestations of these AZT treatments included splenic enlargement and reduced hematocrit, although all treated, uninfected mice survived the treatments, gained weight, and displayed no significant effects on enumeration of T and B cells.

A sensitive immunoenzymometric assay for 2',5'-oligoadenylate. Detection of elevated 2',5'-oligoadenylate synthetase in human peripheral mononuclear cells.

A competition immunoenzymometric assay for 2',5'-oligoadenylate was developed and employed to measure the interferon-inducible enzyme 2',5'-oligoadenylate synthetase in cell extracts. Microtiter plates coated with a novel conjugate of p5'A2'p5'A2'p5'A and N-(2-aminoethyl)-carbamylmethylated-Ficoll (AECM-Ficoll) bound rabbit polyclonal or mouse monoclonal antibody directed against 2',5'-oligoadenylate. Binding was inhibited by soluble 2',5'-oligoadenylate. Estimates of 2',5'-oligoadenylate concentrations based on inhibition of antibody binding compared favorably with those obtained using a protein synthesis inhibition assay. Low concentrations of 2',5'-oligoadenylate synthesized in vitro by extracts of human peripheral mononuclear cells were conveniently estimated using less than or equal to 10(6) cells. Virtually identical results were obtained when either total extract or synthetase bound to poly(I) . poly(C)-agarose was used for the in vitro incubation. When peripheral mononuclear cells were incubated in vitro with interferon, the normally low levels of 2',5'-oligo(A) synthetase rose dramatically. The assay was employed to measure synthetase levels in peripheral mononuclear cells isolated from patients with systemic lupus erythematosus. Some of these patients were found to have elevated levels of 2',5'-oligoadenylate synthetase.

Computer-assisted structure-activity correlations of halodideoxynucleoside analogs as potential anti-HIV drugs.

Analysis of the structure-anti-HIV activity correlations of halo dideoxynucleosides (ddN's) in the public domain was accomplished through computer substructure searching, retrieval and sorting of in vitro anti-HIV data. In the survey, selectivity index (ratio of cytotoxicity to the potency in inhibiting HIV replication in vitro) was used to rank compounds in congeneric groups. Factors contributing to the anti-HIV activity, e.g. the nature and location of the halogen on the sugar or the base and its stereochemical configuration, could not be generalized for all the halogenated ddN's. Conclusions were drawn for specific classes within the pyrimidine and purine series, with compounds further divided into halo substitutions at the sugar 2',3',4'-positions or in the pyrimidine or purine ring systems. At the 3'-position, only a fluoro substitution enhanced the activity of the dideoxypyrimidine nucleosides. A 2'-ara fluoro substituent increased the activity of purine ddN's but decreased activity of pyrimidine ddN's. Halogenation of the side chain in acyclic adenine and 2,6-diaminopurine nucleosides improved their anti-HIV activity. Halo substitution at the 6- or 2'-ara position of selected purine ddN's resulted in compounds with increased lipophilicity, chemical stability and retention of anti-HIV activity. The number of halodideoxynucleosides tested as anti-HIV reagents suggested that this class of compounds is well studied.

Recent advances in AIDS vaccine research and development.

There is an urgent need for a prophylactic vaccine to protect individuals from AIDS and to help abate the growing epidemic. In October 1993, the Conference on Advances in AIDS Vaccine Development reviewed the state-of-the-art in vaccine research and confirmed both the progress that has been made and the challenges that remain. Approximately 12 candidate vaccines are now in phase I/II clinical trials. To date, these products appear to be safe and capable of eliciting immune responses in vaccinees. Other vaccine strategies in development include the use of new formulations and the design of vaccine products capable of inducing a mucosal immune response. Progress has also been made in the establishment of domestic and international sites at which efficacy trials can be conducted when appropriate vaccine candidates are identified, and preparatory activities at these sites are ongoing. The possibility that one or more candidates may enter efficacy trials within the next 2 years underscores numerous issues that must be considered in preparation for these trials. These include the importance of ease of vaccine administration and cost, and an array of social, legal, and ethical issues of concern to those individuals who will be asked to participate in efficacy trials. The purpose of this article is to highlight recent advances in vaccine research and development and to define the complex factors that will impact the NIAID's position on advancing candidates into phase III trials.

HIV vaccine development.

Optimism prevails that a safe and at least partially effective HIV vaccine will be identified within this decade. Public, philanthropic and private sector efforts to expand the development pipeline and to indude candidates based on diverse HIV subtypes have proved successful. Yet both scientific and logistical obstacles remain. No vaccine candidate yet induces broadly neutralizing antibodies. The type, level, location and durability of immune responses necessary for protection remain unknown. For those vaccines that may not prevent HIV infection but control replication and prevent disease, the issue of transmissibility must be addressed. Other challenges indude improving infrastructure and research capabilities and establishing or strengthening regulatory agencies in developing countries. Another key issue is ensuring access to successful vaccines, which will require large-scale manufacturing and development of policies and processes to distribute vaccine to those most in need.

Immunization. Update: search for an AIDS vaccine.

Identifying a successful HIV preventive vaccine is among the highest research priorities of the US NIH. While therapies for HIV have brought hope to those who are already HIV-infected, stopping the worldwide epidemic will require safe, effective HIV vaccines. Here, we describe scientific and other obstacles to attaining that goal and provide a brief synopsis of clinical trial results, recent preclinical results, and future priorities.

Optimism is growing as researchers move toward an AIDS vaccine.

Slow to start, the race for an effective AIDS vaccine now has more than 20 contenders, including some novel approaches that incorporate genetic engineering and the use of vectors, such as a canarypox that doesn't cause disease in humans. Researchers and public health officials say they are more optimistic than ever about the possibility of bringing an AIDS vaccine to market.

The role of nonhuman primate models in AIDS vaccine development.

Although animal models have been useful in guiding vaccine development, HIV/AIDS models have not yielded a clear correlate of immunity nor given consistent results on the potential efficacy of various vaccine approaches. Further development and improved uniformity in the use of animal models would maximize their potential to meet the urgent worldwide need for a safe and effective HIV vaccine.

Progress in AIDS vaccine development.

Because of a unique combination of challenges facing human immunodeficiency virus vaccine developers, a number of traditional and novel vaccine designs are being evaluated essentially in parallel. Monomeric proteins, poxvirus vectors, peptides, and particle-based candidate vaccines have entered or will soon enter human trials. Other designs are at earlier stages of development. All candidates evaluated to date in phase I/II human trials have proven safe and immunogenic. One or more of the most promising designs will soon progress to 'test of concept' clinical trials to determine efficacy.

HIV vaccines: problems and prospects.

Several lines of evidence now argue strongly that a successful HIV vaccine does not need to block infection completely. It has to mimic what already occurs in a minority of unvaccinated individuals--namely, rapid clearance of infection or reduction of viral load to a level that does not produce symptoms or permit transmission to others. The various vaccine candidates are reviewed.

A misaligned double-stranded RNA, poly(I).poly(C12,U), induces accumulation of 2',5'-oligoadenylates in mouse tissues.

2',5'-Oligoadenylate synthetase was induced 3-2000-fold in spleen, liver, kidney and brain of NIH Swiss mice injected intravenously with 2-200 micrograms of the misaligned dsRNA, poly(I).poly(C12,U). Levels of 2',5'-oligoadenylates extracted from these tissues were also elevated, although the amount of 2',5'-oligoadenylates extracted did not correlate directly with the amount of enzyme present. These results suggest that double-stranded portions of the misaligned polymer survived intracellularly and activated the 2',5'-oligoadenylate synthetase, and that the level of dsRNA may contribute to the control of 2',5'-oligoadenylate metabolism.